Bladder cancer (BCa) is the fourth malignancy affecting the genitourinary system in United States. With estimated, 73,510 new cases and 14,880 deaths from BCa in 2014 in The United States. Almost 25-40% of patients present with muscle invasive disease, and approximately 50% will harbor distant metastases. Even after radical eradication of the primary tumor, recurrence is common and survival rates are less than 60%. Prognostic and therapeutic approaches are hampered by presentation with an already established disease, lack of appropriate normal controls and predictive/prognostic biomarkers with no approved new drugs in the past 30 years. Secreted Protein Acidic and Rich in Cysteine (SPARC) is a matricellular glycoprotein that exhibits contextual expression and functions maintaining tissue homeostasis. SPARC is expressed and secreted by malignant and/or tumor-associated stromal cells and transduces intra and extracellular signals, orchestrating tumor progression. The role of SPARC in different cancers is unfolding and its role in BCa is still elusive. The overall goal of this proposal is to investigate the expression and disease association of SPARC in BCa. My preliminary data show that SPARC expression in BCa cell lines was negatively associated with their in vitro proliferation and in vivo tumorigenicity. Chemical-carcinogenesis model of BCa, in SPARC knockout and wild-type mice showed that urothelial carcinogenesis and progression were significantly accelerated in KO mice. Inflammation is the forerunner of the disease and was accompanied by accelerated preneoplasia and overt neoplasia. The overall hypothesis is that SPARC exhibits differential expression and functions in BCa microenvironment. Our specific aims are: (i) Characterize the interactions between cancer cells and macrophages and their regulation by SPARC. The hypothesis for Aim#1 is that SPARC plays an important anti-inflammatory role regulating cancer cell-macrophage crosstalk. (ii) Define the molecular basis for SPARC-mediated cell cycle arrest of bladder cancer cells. The hypothesis for Aim#2 is that SPARC restrain cancer cell proliferation through cell cycle arrest through autocrine and paracrine effects involving cell surface receptor(s). (iii) Evaluate the functional and predictive relevance of SPARC in human and murine BCa. The hypothesis for Aim#3 is that SPARC is differentially expressed in cancerous versus non-cancerous cells as a function of grade and stage. Our proposal includes cell, molecular, chemoproteomic, genetic models and human tumor tissues aimed at understanding the regulation, function and disease aspects of SPARC in BCa. Fundamental findings that we hope to show include a function for SPARC regulating the rate limiting steps in BCa pathobiology, namely inflammation and cell cycle regulation.